open access publication

Article, 2023

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy

In: npj Genomic Medicine, ISSN 2056-7944, Volume 8, 1, Page 28, 10.1038/s41525-023-00370-z

Contributors (36)

Roshandel, Delnaz (0000-0002-4902-8587) [1] Sanders, Eric J. [1] [2] Shakeshaft, Amy (0000-0003-1412-5413) [3] Panjwani, Naim (0000-0001-7551-0759) [1] Lin, Fan [1] Collingwood, Amber [3] Hall, Anna [3] Keenan, Katherine [1] Deneubourg, Celine (0000-0002-8854-6619) [3] Mirabella, Filippo [3] Topp, Simon [3] Zarubova, Jana [4] Thomas, Rhys Huw (0000-0003-2062-8623) [5] [6] Talvik, Inga [7] Syvertsen, Marte Roa (0000-0003-2182-4247) [8] Striano, Pasquale (0000-0002-6065-1476) [9] [10] Smith, Anna B. [3] Selmer, Kaja Kristine (0000-0003-4871-112X) [11] Rubboli, Guido (0000-0002-5309-2514) [12] [13] Orsini, Alessandro [14] Ng, Ching Ching [15] Møller, Rikke Steensbjerre (0000-0002-9664-1448) [13] [16] Lim, Kheng-Seang (0000-0002-2787-2365) [15] Hamandi, Khalid (0000-0001-7116-262X) [17] [18] Greenberg, David A. [19] Gesche, Joanna (0000-0002-0546-4619) [20] Gardella, Elena (0000-0002-7138-6022) [13] [16] Fong, Choong Yi [15] Beier, Christoph Patrick P (0000-0001-8268-1492) [20] Andrade, Danielle M. [2] [21] Jungbluth, Heinz (0000-0002-7159-3427) [3] [22] Richardson, Mark Philip (0000-0001-8925-3140) [3] [23] Pastore, Annalisa [3] Fanto, Manolis (0000-0001-7807-2563) [3] Pal, Deb K (Corresponding author) [3] [23] Strug, Lisa Joanna (0000-0003-0503-9740) (Corresponding author) [1] [2]

Affiliations

  1. [1] Hospital for Sick Children
  2. [NORA names: Canada; America, North; OECD]
  3. [2] University of Toronto
  4. [NORA names: Canada; America, North; OECD]
  5. [3] King's College London
  6. [NORA names: United Kingdom; Europe, Non-EU; OECD]
  7. [4] University Hospital in Motol
  8. [NORA names: Czechia; Europe, EU; OECD]
  9. [5] National Health Service England
  10. [NORA names: United Kingdom; Europe, Non-EU; OECD]

Abstract

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10−9) and 10p11.21 (P = 3.6 × 10−8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10−3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10−3) and increased seizure-like events (P = 6.8 × 10−7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10−3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Keywords

Drosophila model, Drosophila polypeptides, JME, NLGN1, PTPRD, RNAi knockdown, SLCO5A1, SNPs, analysis, anion transporters, assembly genes, associated SNPs, association, attention deficit hyperactivity disorder, behavior, bipolar disorder, cerebral cortex, characterisation, colocalization, components, cortex, disease, disorders, elevated impulsivity, enrichment, epilepsy, etiology, events, expression quantitative trait loci, function, functional characterisation, genes, health, high homology, homology, hyperactivity disorder, impulsivity, impulsivity scores, juvenile myoclonic epilepsy, key component, knockdown, loci, loss, mechanism, model, myoclonic epilepsy, organic anion transporters, pathway analysis, polygenic risk scores, polypeptide, quantitative trait loci, results, risk score, scores, seizure mechanisms, seizure-like events, trait loci, transporters, wide association

Funders

  • Engineering and Physical Sciences Research Council
  • National Institute for Health and Care Research
  • Ministry of Education, Universities and Research
  • Epilepsy Research UK
  • The Research Council of Norway
  • Action Medical Research
  • Medical Research Council
  • Canadian Institutes of Health Research
  • Health and Care Research Wales
  • European Commission
  • Eisai (Japan)
  • Canada Research Chairs